Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used to treat a variety of malignant and non-malignant disorders, and involves the transfer of stem cells from the bone marrow, blood, or umbilical cord from a non-identical donor. The widespread application of this procedure is limited by the high rate of graft-versus-host disease (GVHD), a life-threatening condition that is mediated by alloreactive T cells from the transplant. Improving the procedure is dependent on identifying the mechanisms that contribute to this damaging T cell reactivity. Autophagy, a cellular process by which cytosolic material is delivered to the lysosome for degradation, is receiving increasing attention as a pathway that contributes to a balanced immune response. Additionally, a highly common polymorphism in the autophagy gene Atg16L1 is associated with inflammatory bowel disease (IBD), suggesting a role for this gene and pathway in inflammatory conditions. To test the role of Atg16L1 in GVHD, we performed an allo-HSCT using Atg16L1 mutant recipient mice and found that deficiency in this gene significantly increased lethality and disease following the transplant This enhanced GVHD is associated with increased donor-derived T cell proliferation and intestinal barrier disruption, most likely due to an unexpected role of Atg16L1 in suppressing dendritic cell hyperactivation. Moreover, preliminary data indicates that the IBD risk polymorphism of Atg16L1 is associated with a higher incidence of transplant-related mortality in humans, thus supporting our observations in a preclinical mouse model. In this proposal, we will further define the role of Atg16L1 and autophagy during allo-HSCT and elucidate mechanism. We will identify the factors that contribute to enhanced GVHD, examine graft-versus-tumor reactions, and understand how Atg16L1 suppresses dendritic cell hyperactivity. We anticipate that these results will yield significant insight into allo-HSCT as well as reveal processes that ae fundamental to inflammatory disease.